TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613], Crohn's disease [Van Assche, G.; Rutgeerts, P.; Exp. Opin. Invest. Drugs, 2000, 9, 103; Rutgeerts, P.; Baert, F. Drugs of Today, 2000, 36(Suppl. G, Doctor in Focus), 59], psoriatic arthritis [Kreuger, G.; Callis, K.; Archives of Dermatology, 2004, 140, 218], psoriasis [Kristensen, M.; Chu, C. Q.; Eedy, D. J.; et al.; Clin. Exp. Immunol., 1993, 94, 354], vasculitis [Lorenz, H.-M.; Kalden, J. R.; Arthritis Res., 2002, 4(suppl 3), S17], ankylosing spondylitis [Wendling, D.; Toussirot, E.; Exp. Opin. Pharmacotherapy, 2004, 5, 1497], septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91; Robertshaw, H. J.; Brennan, F. M.; Br. J. Anaesth., 2005, 94, 222], graft rejection [Piguet, P. F.; Grau, G. E.; et al. J. Exp. Med. 1987, 166, 1280], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505], anorexia, inflammation [Ksontini, R.; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479; Feldman, A. M.; Combes, A.; Wagner, D,; J. Am. Coll. Cardiol., 2003, 35, 537; Mamoru, S.; Iwasaka, J.; Nakamura, M.; et al.; Eur. J. Heart Failure, 2004, 6, 869], post-ischaemic reperfusion injury [Gilles, S.; Zahler, S.; Welsch, U.; et al.; Cardiovascular Res., 2003, 60, 608], inflammatory disease of the central nervous system [Moro, M. A.; Hurtado, O.; Cardenas, A; et al.; Neurosignals, 2003, 12, 53], inflammatory bowel disease and ulcerative colitis [Colon, A. L.; Menchen, L. A.; Hurtado, O.; De Cristobal, J.; Lizasoain, I.; Leza, J. C.; Lorenzo, P.; Moro, M. A.; Cytokine, 2001, 16, 220; Kirkegaard, T.; Pedersen, G.; Saermark, T.; Brynskov, J.; Clin. Exp. Immunol.; 2004, 135, 146], insulin resistance and diabetes [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87; Hotamisligil, G. S.; Spiegelman, B. M.; Diabetes, 1994, 43, 1271; Morimoto, Y.; Nishikawa, K.; Ohashi, M. Life Sci., 1997, 61, 795], chronic obstructive pulmonary disease (COPD) and asthma [Trifilieff, A.; Walker, C.; Keller, T.; Kottirsch; Neumann, U.; Brit. J. Pharmacol., 2002, 135, 1655], stroke [Wang, X.; Feuerstein, G. Z.; Xu, L.; et al.; Mol. Pharmacol., 2004, 65, 890; Wang, X.; Xu, L.; Feuerstain, G. Z.; et al. Circulation, 2003, 108 (17 Supp.), iv-103; Hallenback, J. M.; Nature Medicine, 2002, 8, 1363.], pneumococcal meningitis [Meli, D. N.; Loeffler, J. M.; Baumann, P. et al.; J. Neuroimmunology, 2004, 151, 6], tumor metastasis [Nelson, A. R.; Fingleton, B.; Rothenberg, M. L.; et al.; J. Clin. Oncol., 2000, 18, 1135], multiple sclerosis [Clements, J. M.; Cossins, J. A.; Wells, G. M.; et al.; J. Neuroimmunol., 1997, 74, 85]] and HIV infection [Peterson, P. K.; Gekker, G.; et al. J. Clin. Invest 1992, 89, 574; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15 (6), 533], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230, 630]. For example, research with anti-TNF-α antibodies and transgenic animals has demonstrated that blocking the formation of TNF-α inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (October), au197-M2Z]. This observation has been extended to humans as well [“TNF-α in Human Diseases”, Current Pharmaceutical Design, 1996, 2, 662].
(3S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxamide (apratastat) is a potent, reversible, and competitive inhibitor of TACE in vitro having the structure below:
Apratastat inhibits TNF-α secretion by human synovium tissue explants from patients suffering from rheumatoid arthritis and is a potent TNF-α inhibitor in murine and primate lipopolysaccharide (LPS) models. These data demonstrate that apratastat has the potential for treating and/or inhibiting disease states mediated by TACE. The preparation of apratastat was first disclosed in U.S. Pat. No. 6,225,311, the entire disclosure of which is hereby incorporated by reference.
It is well known that the crystalline polymorph form of a particular drug is often an important determinant of the drug's ease of preparation, stability, solubility, storage stability, ease of formulation and in vivo pharmacology. Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular polymorph form. In cases where two or more polymorph substances can be produced, it is desirable to have a method to make polymorphs in pure form. In deciding which polymorph is preferable, the numerous properties of the polymorphs must be compared and the preferred polymorph chosen based on the many physical property variables. It is entirely possible that one polymorph form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different polymorph may be preferred, for example, for greater solubility and/or superior pharmacokinetics.
Because improved drug formulations showing, for example, better bioavailability or better stability are consistently sought, there is an ongoing need for new or purer polymorphic forms of drug molecules. The polymorphs of apratastat described herein help meet these and other needs.